Use of 2,5-dihydroxybenzene derivatives for treating dermatitis

ABSTRACT

The present invention relates to the use of a 2,5-dihydroxybenzene derivative represented by Formula (I) or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof for the therapeutic and/or prophylactic treatment of, inter alia, dermatitis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of and claims the benefit of priorityof pending U.S. application Ser. No. 14/863,896, filed on Sep. 24, 2015,which is a continuation of U.S. application Ser. No. 14/333,729, filedon Jul. 17, 2014 and issued as U.S. Pat. No. 9,192,592 on Nov. 24, 2015,which is a continuation of U.S. application Ser. No. 13/209,803, filedon Aug. 15, 2011 and issued as U.S. Pat. No. 8,815,836, issued on Aug.26, 2014, which is a continuation of U.S. application Ser. No.11/839,512, filed on Aug. 15, 2007, now abandoned, which claims thebenefit of priority under 35 U.S.C. § 119 of ES Application No.P200602219, filed Aug. 16, 2006 and of ES Application No. P200701857,filed Jul. 2, 2007. The foregoing applications, and all documents citedtherein, are hereby incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the use of 2,5-dihydroxybenzenederivatives to manufacture medicaments useful to prevent skin aging dueto exposure to ultraviolet B rays (UVB), or to exposure to sun rays ingeneral, to treat pathologies associated to said skin photoaging such asseborrheic keratosis, as well as to treat dermatitis.

BACKGROUND OF THE INVENTION

Chronic exposure to ultraviolet B rays (UVB: 290-320 nm wavelength), orsolar rays, in general (comprising, among other wavelengths, that of UVBradiation) produces skin aging (photoaging) due to the accumulation ofDNA damage and on the structural proteins of the skin, evidencing in theform of fine wrinkles, laxity with loss of skin elasticity, elastosis,yellowish staining with localized areas of melanin hyperpigmentation(solar, actinic or senile lentigo). Besides, skin photoaging isassociated with the appearance of comedoes that are more evident in the“cutis romboidalis” at the rear part of the neck. In the histologicaltest, an epidermic atrophy and degenerative changes in elastic fibers ofthe dermis may be observed (Pearse A D, Gaskell S A, Marks R. J InvestDermatol 1987; 88 83-87; Berton T R, Mitchell D L, Fischer S M,Looniskar M F. J Invest Dermatol 1997; 109: 340-347). Furthermore,chronic exposure to UVB rays is a risk factor for the appearance ofbenign lesions, such as seborrheic keratosis, and premalignant lesionssuch as actinic keratosis (Kripke M L. Cancer Res 1994; 54: 6102-6105).Currently, there is no effective treatment for skin photoaging (DermatolSurg. Special Issue: Cosmeceuticals. Invited editors: Draelos Z D, BrodyH J. 2005).

On the other hand, the hair follicle is the functional unit for hairelongation. Hirsutism is a clinical condition in which there in anexcessive hair growth with an androgenic-type pattern (face, thorax,areolas, linea alba, lower part of the back, buttocks, limbs andexternal genitals) produced by an increase in the androgenic activity.Hypertricosis is a condition in which there is an excessive hair growthin areas sensitive and non-sensitive to androgens.

Obesity is a disease produced when the energy intake exceeds andproduces an excess of adipose tissue. This process is regulated by thecontrol on the intake, on the energy expenditure and efficiency and onthe adipogenesis). (Gregoire F M. Exp Biol Med, 2001, 226: 997-1002;Palou A et al. Eur J Nutr, 2000, 39: 127-144). Prevention and/ortreatment of obesity is a very important factor to reduce morbidity andmortality rates associated to cardiovascular disorders and to type 2diabetes, which represent a high health and social cost inindustrialized countries. Currently, there is no effective treatment forobesity. The effective therapies to treat obesity should interfere withthe development of adipose tissue. To increase the adipose tissue mass,it is essential that preadipocytes are differentiated in a matureadipocyte phenotype. Besides morphological changes, the differentiationprocess of preadipocyte into adipocyte is accompanied by metabolicprocesses such as the capacity of storing energy in the form oftriglycerides (McDougald O A, Lane M D. Annu Rev Biochem, 1995, 345-373;Spiegelman B M, Flier J S. Cell 1996, 87: 377-389). Therefore, thepharmacological inhibition of the differentiation of preadipocytes intoadipocytes represents a therapeutic strategy to treat obesity.

There is a need to find alternative treatments to the current ones forskin aging and photoaging, both from the aesthetic and therapeuticpoints of view, based on the use of active principles.

SUMMARY OF THE INVENTION

Surprisingly, the inventors have found that 2,5-dihydroxybenzenederivatives, the pharmaceutically acceptable salts and solvates thereof,as well as isomers and prodrugs thereof are useful to prevent and/ortherapeutically treat skin aging due to exposure to ultraviolet rays B(UVB), or to exposure to sun rays in general, to treat pathologiesassociated to said skin photoaging such as seborrheic keratosis. Inaddition said derivatives are useful to prevent and/or therapeuticallytreat dermatitis.

In certain embodiments, the invention provides a method for thetreatment or prophylaxis of dermatitis, comprising administering to asubject in need thereof, an effective amount of a 2,5-dihydroxybenzenederivative represented by Formula (I) or a pharmaceutically acceptablesalt, solvate, isomer, or prodrug thereof, wherein the compound ofFormula (I) is:

wherein:

-   -   R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Z;    -   Y is —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, or —PO₃R₃,        wherein when Y is —SO₃H, —SO₃ ⁻.X⁺ or —SO₃R₃, then R₉ and R_(9′)        are independently selected from —OH and —OR₂, wherein at least        one of R₉ and R_(9′) is a substituted or unsubstituted        alkylsulfonyloxy group, a substituted or unsubstituted        arylsulfonyloxy group, a substituted or unsubstituted        alkylcarbonyloxy group or a substituted or unsubstituted        arylcarbonyloxy group;    -   Z is —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃, —CO₂H,        —CO₂ ⁻.X⁺ or —CO₂R₃;    -   X⁺ is an organic cation or an inorganic cation, such that the        general charge of the compound is neutral;    -   R₉ and R_(9′) are independently selected from —OH and —OR₂,        wherein when R₉ and R_(9′) are both —OR₂, then said R₉ and        R_(9′) can be the same or different;    -   R₂ is a substituted or unsubstituted alkyl group, a substituted        or unsubstituted aryl group, a substituted or unsubstituted        alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl        group, a substituted or unsubstituted alkylcarbonyl group or a        substituted or unsubstituted arylcarbonyl group;    -   R₃ is a substituted or unsubstituted alkyl group or a        substituted or unsubstituted aryl group;    -   a is a number selected from 0, 1, 2, 3, 4, 5 and 6; and    -   p is an integer selected from 0, 1, 2, 3, 4, 5 and 6.

In certain embodiments, R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Y. In otherembodiments, Y is selected from —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃. In yet otherembodiments, R₃ is selected from methyl and ethyl. In some embodiments,R₉ and R_(9′) are, independently, a substituted or unsubstitutedalkylsulfonyloxy group, a substituted or unsubstituted arylsulfonyloxygroup, a substituted or unsubstituted alkylcarbonyloxy group or asubstituted or unsubstituted arylcarbonyloxy group. In some embodiments,R₂ is selected from methylcarbonyl, phenylsulfonyl,4-methylphenylsulfonyl, benzylsulfonyl, benzyl and phenyl

In certain embodiments, the compound of Formula (I) is selected from thegroup consisting of:5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-hydroxy-5-{([(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid;2,5-bis(acetyloxy)benzenesulfonic acid;5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2,5-bis {[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;2,5-bis(acetyloxy)benzenehomosulfonic acid;3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic acid);3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid;3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceuticallyacceptable salts, solvates, and prodrugs thereof.

In certain embodiments, the compound of Formula (I) is selected from:2-(acetyloxy)-5-hydroxybenzenesulfonic acid,5-(acetyloxy)-2-hydroxybenzenesulfonic acid and2,5-bis(acetyloxy)benzenesulfonic acid.

In certain embodiments, the invention provides a method for thetreatment or prophylaxis of dermatitis, wherein the dermatitis isselected from the group consisting of: actinic dermatitis, allergiccontact dermatitis, atopic dermatitis, carcinomatous dermatitis, contactdermatitis, diaper dermatitis, stasis dermatitis, neurodermatitis,dermatomyositis and radiation-induced dermatitis.

Advantageously, a compound of Formula (I) is administered topically. Incertain embodiments, the compound of Formula (I) is administered orally,buccally, transdermally, by inhalation, or otically.

In certain embodiments, the invention provides a method for thetreatment or prophylaxis of dermatitis further comprising administrationof at least one additional therapeutic agent.

Examples of suitable additional therapeutic agents include diclofenac,T4 endonuclease, isotretinoin, acitretin, cidofoir, a corticosteroid, anantibiotic, an analgesic, an immunomodulator, including oralimmunomodulator such as tacrolimus and pimecrolimus, and topicalimmunomodulators; an immunosuppressant, an anti-angiogenic, includinganti-VEGF, anti-FGF, anti-EGF and anti-HGF; a leukotriene modifier, anaminosalicylate, an anesthetic, a non-steroidal anti-inflammatory, amodifier of a solubilized interleukin receptor, an inhibitor of atyrosine-kinase receptor, a protein kinase C inhibitor, and acombination of two or more thereof.

In certain embodiments, the invention provides for administration of acompound of Formula (I) for the treatment and/or prophylaxis ofdermatitis, wherein the compound is administered at least once per week.In other embodiments, the compound is administered at least once per dayor at least twice per day.

In certain embodiments, a compound of Formula (I) is present in apharmaceutical composition in an amount of at least about 1% w/w. Inother embodiments, the compound is present in a pharmaceuticalcomposition in an amount of at least about 2.5% w/w, at least about 5%w/w, at least about 10% w/w, or at least about 15% w/w.

In yet other embodiments, a compound of Formula (I) is administered overa period of at least about one week. In certain embodiments, thecompound is administered over a period of at least about four weeks.

These and other aspects of the present invention are described in detailherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Inhibitory effect of 2,5-dihydroxybenzenesulfonic acid (DHBS) ondermatitis induced by the application of benzalkonium chloride on therat ears. Dermatitis was induced in both ears, and only the right earwas treated topically with a cream containing 5% DHBS; the left ear wasused as control. The intravenous injection of Evans blue dye revealedthe extent of dermatitis in the ears. The application of the creamcontaining DHBS remarkably reduced dye extravasation caused by thedermatitis, as shown in photographs (A-F) of the treated ears in the 6rats that, 4 hours after dermatitis induction, exhibited a coloredextent lower than untreated ears.

FIG. 2. Quantification of the inhibitory effect of2,5-dihydroxybenzenesulfonic acid (DHBS) on dermatitis induced by theapplication of benzalkonium chloride on the ears of the rats shown inFIG. 1. The abscissa axis represents the percentage of the blue-coloredarea compared to the total area of the ear, as a marker of thedermatitis extent. Data is expressed as the mean±SEM of thecorresponding values of the six rats shown in FIG. 1. As shown in thegraphs, topical application of 5% DHBS (black bars) significantlyreduced dermatitis extent as observed 4 hours later (A) and 24 hours (B)after induction thereof.

FIG. 3. Appearance of two rat ears on which benzalkonium chloride wasapplied to induce dermatitis. One of the rats (A), was treated topicallywith glycerol in both ears, while the other rat (B) was treatedtopically with a solution of glycerol containing 2.5% of2,5-diacetoxybenzenesulfonic acid (DABS). The erythema caused by thedermatitis is milder in the mouse treated with DABS.

FIG. 4. Representative examples of the histological study of the effectof a topical treatment with 2.5% 2,5-diacetoxybenzenesulfonic acid(DABS) on the dermatitis induced by benzalkonium chloride on the ear ofthe rat. The microphotograph shows a clear tissular edema on the ear ofa rat with dermatitis and treated only with the vehicle (anhydrousglycerol) (a). This edema is not observed in a rat with dermatitis buttreated with 2.5% DABS in glycerol (b). In the ear treated with thevehicle, a considerable leukocyte infiltration in the tissue (c) may beobserved, and it is noticeably milder in the ear of a rat treatedtopically with 2.5% DABS (d). The magnification of the area marked witha box in c and d shows that in the capillaries of the rat treated withvehicle there are granulocytes adhered to the endothelial cells thatroll and extravasate to infiltrate the surrounding tissue (e), this isnot observed in the vessels of the rat treated with DABS (f). Thetissues were fixed 24 hours after dermatitis induction.

FIG. 5. Effect of the topical treatment with2,5-dihydroxybenzenesulfonic acid (DHBS), 2,5-diacetoxybenzenesulfonicacid (DABS) or vehicle (anhydrous glycerol) over the increase of themyeloperoxidase (MPO) activity as a result of dermatitis induced bybenzalkonium chloride on the ear of the rat. Once dermatitis wasinduced, the ears were treated with vehicle (anhydrous glycerol), a 5%DHBS cream, or with 2.5% DABS solution in anhydrous glycerol.Twenty-four hours after the dermatitis induction, the ears were removedand frozen. The control group corresponds to ears of rats in whichdermatitis had not been induced. The MPO activity is expressed as themean±SEM of the absorbance at 460 nm normalized by the mg of the tissueof the corresponding ear. The number of animals used in each group isstated between brackets. ** indicates p<0.01 vs. control, †p<0.05,††p<0.01 vs. vehicle.

FIG. 6. Inhibitory effect of 2-acetoxy-5-hydroxybenzenesulfonic acid(2A-5HBS) on dermatitis induced by the application of benzalkoniumchloride on the rat ears. Dermatitis was induced in both ears, and onlythe right ear was treated topically with a solution containing 5%2A-5HBS in glycerol; the left ear was used as control. The intravenousinjection of Evans blue dye revealed the extent of dermatitis in theears. The application of the solution containing 5% 2A-5HBS remarkablyreduced dye extravasation caused by the dermatitis, as shown inphotographs (A-E) of the treated ears in the 5 rats that, 24 hours afterdermatitis induction, exhibited a colored extent lower than untreatedears.

FIG. 7. Inhibitory effect of 5-acetoxy-2-hydroxybenzenesulfonic acid(5A-2HBS) on dermatitis induced by the application of benzalkoniumchloride on the rat ears. Dermatitis was induced in both ears, and onlythe right ear was treated topically with a solution containing 5%5A-2HBS in glycerol; the left ear was used as control. The intravenousinjection of Evans blue dye revealed the extent of dermatitis in theears. The application of the solution containing 5% 5A-2HBS remarkablyreduced dye extravasation caused by the dermatitis, as shown inphotographs (A-D) of the treated ears in the 4 rats that, 24 hours afterdermatitis induction, exhibited a colored extent lower than untreatedears.

FIG. 8. Quantification of the inhibitory effect of2-acetoxy-5-hydroxybenzenesulfonic acid (2A-5HBS) on dermatitis inducedby the application of benzalkonium chloride on the ears of the ratsshown in FIG. 6. The abscissa axis represents the percentage of theblue-colored area compared to the total area of the ear, as a marker ofthe dermatitis extent. Data are expressed as the mean±SEM of thecorresponding values from the five rats shown in FIG. 6. As shown in thegraphs, topical application of 5% 2A-5HBS (stripped bar) significantlyreduced dermatitis extent 24 hours after induction thereof.

FIG. 9. Quantification of the inhibitory effect of5-acetoxy-2-hydroxybenzenesulfonic acid (5A-2HBS) on dermatitis inducedby the application of benzalkonium chloride on the ears of the ratsshown in FIG. 7. The abscissa axis represents the percentage of theblue-colored area compared to the total area of the ear, as a marker ofthe dermatitis extent. Data are expressed as the mean±SEM of thecorresponding values from the four rats shown in FIG. 7. As shown in thegraphs, topical application of 5% 2A-5HBS (gray bar) significantlyreduced dermatitis extent 24 hours after induction thereof.

FIG. 10. Co-crystallized potassium 5-acetoxy-2-hydroxybenzenesulfonicacid with fibroblast growth factor-1. The electron density of thecompound, contoured at 1σ (panel C), enables the localization andrecognition of the compound orientation regarding the protein (panels Aand B), as well as the confirmation that the compound maintains theacetoxyl group in position 2 when it binds to the protein. The compoundis located at a site very close to the site that, as described, isoccupied by the 2,5-dihydroxybenzenesulfonic acid, which aromatic ringforms a cation-n bond with the N^(ε) group of lysine 132, marked inpanel A as reference. Panel B shows, in the form of a mesh, the Van derWaals volume of 2-acetoxy-5-hydroxybenzenesulfonic acid, overlapped toits representation in the form of rods. In panels A and B, the proteinsurface is colored according to its electrostatic potential (light grey:negative charge; dark grey: positive charge; white: lack of charge).

FIG. 11. Co-crystallized potassium 5-acetoxy-2-hydroxybenzenesulfonicacid with fibroblast growth factor-1. The electron density of thecompound, contoured at 1σ (panel C), enables the localization andrecognition of the compound orientation regarding the protein (panels Aand B) as well as the confirmation that the compound maintains theacetoxyl group in position 5 when it binds to the protein. The compoundis located at a site very close to the site that, as described, isoccupied by the 2,5-dihydroxybenzenesulfonic acid, which aromatic ringforms a cation-r bond with the N group of lysine 132, marked in panel Aas reference. Panel B shows, in the form of a mesh, the Van der Waalsvolume of 2-acetoxy-5-hydroxybenzenesulfonic acid, overlapped to itsrepresentation in the form of rods. In panels A and B, the proteinsurface is colored according to its electrostatic potential (light grey:negative charge; dark grey: positive charge; white: lack of charge).

FIG. 12. Co-crystallized potassium 5-acetoxy-2-hydroxybenzenesulfonicacid with fibroblast growth factor-1. The electron density of thecompound, contoured at 1σ (panel C), enables the localization andrecognition of the compound orientation regarding the protein (panels Aand B), as well as the confirmation that the compound maintains theacetoxyl group in position 2 when it binds to the protein. The compoundis located at a site very close to the site that, as described, isoccupied by the 2,5-dihydroxybenzenesulfonic acid, which aromatic ringforms a cation-n bond with the N group of lysine 132, marked in panel Aas reference. Panel B shows, in the form of a mesh, the Van der Waalsvolume of 2-acetoxy-5-hydroxybenzenesulfonic acid, overlapped to itsrepresentation in the form of rods. In panels A and B, the proteinsurface is colored according to its electrostatic potential (light grey:negative charge; dark grey: positive charge; white: lack of charge).

DETAILED DESCRIPTION OF THE INVENTION

The definitions of the terms and the chemical groups comprised in theformulas herein are as follows:

The term “patient” refers to animals, preferably mammals, and morepreferably humans, and includes males and females, children and adults.

The expression “effective amount” refers to the amount of compoundand/or composition effective to achieve the desired purpose.

The terms “treat” or “treatment” refer to the prophylactic use ofcompounds or compositions of the present invention to avoid the symptomsof the disease or condition, or the therapeutical use to improve anexisting condition.

“Alkyl” refers to a linear or branched chain hydrocarbon radicalcomprising carbon atoms and hydrogen, with no unsaturations, with one totwelve, preferably one to eight, more preferably one to six carbonatoms, bound to the rest of the molecule by a single bond, for example,methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.

“Alkenyl” refers to a linear or branched chain hydrocarbon radicalcomprising carbon atoms and hydrogen atoms, containing at least oneunsaturation, with two to twelve, preferably two to eight, morepreferably two to six carbon atoms, bound to the rest of the molecule bya single bond.

“Cycloalkyl” refers to a saturated carbocyclic ring having between threeand eight, preferably three to six carbon atoms. They may exhibit abridged structure. Suitable cycloalkyl groups include, but are notlimited to, cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

“Alkynyl” refers to a linear or branched chain hydrocarbon radicalcomprising carbon atoms and hydrogen, containing at least one triplecarbon-carbon bond, whether conjugated or not, with two to twelve,preferably two to eight, more preferably two to six carbon atoms, boundto the rest of the molecule by a single bond such as —CCH, —CH₂CCH,—CCCH₃, —CH₂CCCH₃.

“Aryl” refers to an aromatic hydrocarbon radical containing from six toten carbon atoms such as phenyl or naphthyl.

“Aralkyl” refers to an aryl group bound to the rest of the molecule byan alkyl group such as benzyl and phenetyl.

“Heterocycle” refers to a stable 3 to 15-membered ring comprised ofcarbon atoms and between one and five heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur, preferably a 4 to8-membered ring with two, three or four heteroatoms, more preferably a 5or 6-membered ring with one, two or three heteroatoms. For the purposeof the present invention, the heterocycle may be a monocyclic, bicyclicor tryciclic ring system that may include fused ring systems; bridgedstructures; and the nitrogen, carbon or sulfur atoms in the heterocyclicradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclic radical may be partially or completelysaturated or it may be aromatic. Examples of such heterocycles include,but are not limited to, azepines, benzimidazole, benzothiazole, furan,isothiazole, imidazole, indole, piperidine, piperazine, quinoline,thiadiazol, tetrahydrofuran.

Unless otherwise specified, the alkyl, cycloalkyl, alkenyl, alkynyl,aryl, aralkyl and heterocycle radicals may be optionally substituted byone, two or three substituents such as halo, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, hydroxy, alkoxy, sulfoxy, O-Benzyl, O-Benzoyl,carboxyl, alkylcarboxyl, arylcarboxyl, alkylcarbonyl, arylcarbonyl,cyano, carbonyl, acyl, alkoxycarbonyl, amino, alkylamino, dialkylamino,arylamino, diarylamino, alkylarylamino, imino, alkylsulphinyl, amidyl,carbamoyl, sulfonamido, nitro, nitrite, nitrate, thionitrate andcarboxamido.

The term “alkoxycarbonyl” refers to a compound having the formula—C(═O)O—, where the C-terminal is bound to the molecule and theO-terminal is bound to a carbon atom to form an ester function. Saidcarbon atom may be part of an alkyl, alkenyl, cycloalkyl, alkynyl, aryl,aralkyl or heterocyclic group.

The term “alkoxycarbonylalkyl” refers to a compound of the previouslydefined formula —C(═O)O—, wherein the C-terminal binds to a moleculethrough an alkyl group. The terms “aryloxy- arylalkoxy- oralkylaryloxy-carbonylalkyl” will be understood similarly to“alkoxycarbonylalkyl”.

The term “arylalkyl” refers to an aryl radical, as defined herein, boundto an alkyl radical, as defined herein. The exemplary arylalkyl groupsinclude benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl and the like.

The term “alkylaryl” refers to an alkyl group, as defined herein, towhich an aryl group is bound, as defined herein. The exemplary alkylarylgroups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

The term “alkylsulfonyl” refers to a R₅₀—S(O)₂—, wherein R₅₀ is a loweralkyl group, as defined herein.

The term “arylsulfonyl” refers to a R₅₅—S(O)₂—, wherein R₅₅ is an arylgroup, as defined herein.

The term “alkylsulphinyl” refers to a R₅₅—S(O)₂—, wherein R₅₅ is an arylgroup, as defined herein.

The term “arylsulphinyl” refers to a R₅₅—S(O)₂—, wherein R₅₅ is an arylgroup, as defined herein.

The term “sulfonamide” refers to a —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ andR₅₇ are each independently a hydrogen atom, an alkyl group, an arylgroup, heterocycle, as defined herein, or else R₅₁ and R₅₇ together forma heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group,as defined herein.

The term “alkylsulfonamide” refers to a sulfonamido group, as definedherein, bound to an alkyl group, as defined herein.

The term “arylsulfonamide” refers to a sulfonamido group, as definedherein, bound to an aryl group, as defined herein.

The term “alkylcarbonyl” refers to a R₅₂—C(O)₂—, wherein R₅₂ is an alkylgroup, as defined herein.

The term “arylcarbonyl” refers to the R₅₅—S(O)₂— radical, wherein R₅₅ isan aryl group, as defined herein.

The term “carboxamide” refers to a —C(O)N(R₅₂)(R₅₅) radical, wherein R₅₂and R₅₅ are each independently a hydrogen atom, an alkyl group, an arylgroup or an heterocyclic group, as defined herein or else R₅₁ and R₅₇together form an heterocyclic ring, a cycloalkyl group, or a bridgedcycloalkyl group, as defined herein.

The term “carboxylic ester” refers to —C(O)OR₅₉, wherein R₅₉ is an alkylgroup an aryl group or an heterocyclic group, as defined herein.

The term “alcoxyalkyl” refers to an alcoxy group, as defined herein,bound to an alkyl group, as defined herein. Examples of alcoxyalkylgroups are methoxymethyl, methoxyethyl, isopropoximethyl and the like.

The term “amine” refers to any organic compound containing at least onebasic nitrogen atom.

The term “organic cation” refers to a positively charged organic ion.The exemplary organic cations include ammonium cations unsubstituted orsubstituted with alkyl, primary, secondary or tertiary amines,alkylamines, arylamines, cyclic amines, N,N′-dibenzylethylenediamine,and the like.

The term “inorganic cation” refers to a positively charged metal ion.The exemplary inorganic cations include Group I metal cations such assodium, potassium, magnesium, calcium and the like.

The term “prodrug” refers to compounds that rapidly convert in vive intopharmacologically active compounds. Prodrug design is generally studiedin Hardma et al. (eds.), Goodman and Gilman's The Pharmacological Basisof Therapeutics, 9th ed., pages 11-16 (1996). A thorough study ispresented in Higuchi et al., Prodrugs as Novel Delivery Systems, vol.14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987).

The term “ester derivative of a compound of formula (I)” refers to thecompound of formula (I) wherein at least one of R₉ and R_(9′) is anester group. For example, the ester derivative of 2,5-dihydroxybenzenesulfonic acid or dobesilate ester derivative refers to the compound2,5-dihydroxybenzene sulfonic acid (dobesilate) wherein at least one ofthe hydroxyl groups has been esterified.

The term “ester of a compound of formula (I)” refers to an ester of thesulfonic or carboxylic acid group at position 1. For example, the esterof 2,5-dihydroxybenzenesulfonic acid or ester of dobesilate refers to anester of the sulfonic acid group at position 1.

The compounds of the invention having one or more asymmetric carbonatoms may exist as optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diasteromericracemates. It should be clearly understood that the inventioncontemplates and includes these isomers and mixtures thereof within itsscope.

The term “topical” refers to the administration of a compound byapplying it on the body surface and includes, but is not limited to,transdermal administration and administration through the mucosa.

The term “transdermal” refers to the delivery of a compound that entersinto the bloodstream through the skin.

The expression “through the mucosa” refers to the delivery of a compoundthat enters into the bloodstream through the mucous tissue.

The term “parenteral” refers to the administration of a compound bymeans of a subcutaneous, intravenous, intramuscular, intracardiac,intradermal, intraperitoneal, intrathecal or intrasternal injection; andalso includes local or systemic infusion techniques.

The expression “penetration enhancement” or “permeation enhancement”refers to the increase in the permeability of the skin or mucous tissueto a pharmacologically active compound selected in such a way that itincreases the penetration rate through the skin or mucous tissue.

“Excipients” or “vehicles” refers to the vehicle materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not showharmful interaction with any component of the composition.

The expression “sustained release” refers to the release of an activecompound and/or composition such that the blood levels of the activecompound are maintained within a desirable therapeutic range over aperiod of time. The sustained release formulation may be prepared usingany conventional known method by a skilled in the art in order to obtainthe desired release characteristics.

The term “Dermatitis” refers to a inflammatory skin disease.

“Atopic dermatitis” refers to a chronic disease affecting the skin.Atopic dermatitis is produced by a combination of genetic andenvironmental factors and associated with excessive IgE antibodyformation.

“Contact dermatitis” refers to an inflammation of the skin that isinduced by external contact with substances that damage the skin bydirect chemical action or through an immunological mechanism. Contactdermatitis is associated with lesions produced on the skin uponcontacting an antigen or irritating solution.

“Stasis dermatitis” refers to a dermatitis in which stasis is merely onefactor in eczema of the lower leg; edema of nutritional or other origin,infection, and reaction to topical medicaments are important factors.

“Actinic dermatitis” or “photodermatitis” refer to dermatitis provokedby exposure to sunlight

“Neurodermatitis” refers to a skin disorder of psychosomatic genesis orin which psychological factors play an important part, as when rubbingand scratching induce circumscribed patches of thickened skin.

“Allergic contact dermatitis” refers to an acute inflammatory conditionof the skin following topical exposure to an allergen to which thesubject shows delayed hypersensitivity.

“Carcinomatous dermatitis” refers to an inflammatory alteration of theskin due to underlying carcinoma.

“Diaper dermatitis” refers to any eruption occurring in the skin that isusually covered by the diaper and is often induced by prolonged contactwith urine or feces.

The term “dermatomyositis” refers to a collagen vascular diseasecharacterized by skeletal muscle inflammation and by erythema and edemaof the skin, notably on the eyelids, backs of the hands, and theextensor aspects of the limbs.

“Seborrheic keratosis” refers to non-cancerous growth of the externallayer of the skin.

The term “therapeutic agent” includes any active agent that can be usedto treat or prevent a disease described herein. “Therapeutic agents”include but are not limited to immunomodulatory treatments, such as atacrolimus ointment or a pimecrolimus cream and the like; topicalcorticosteroids (cream, unguents, ointments or gels) or systemiccorticosteroids; topical or systemic immunosupressants, such as, forexample, cyclosporine, metrotrexate, azathioprine, and the like;phototherapy, emollients such as for example, white petrolatum, eucerin,urea cream, mineral oil, aluminum acetate, and the like; barrier creams,such as, for example, zinc oxide paste, and the like; moisturizingagents, such as, for example, menthol, camphor, and the like; localanesthetics, such as, for example, lidocaine, and the like; topicalcorticoids, such as, for example, triamcinolone acetate, and the like;systemic corticoids, such as, for example, prednisone, and the like;antihistamines, such as, for example, diphenhydramine, hydroxyzine, andthe like; podophylline resin, locally applied; cantharin, only combinedwith podophylline; salicylic acid, locally applied; imiquimod;bleomycin; exfoliating agents, such as, for example, alpha hydroxy acids(glycolic acid, salicylic acid, lactic acid), trichloroacetic, phenols(carbolic acid, croton oil, and the like; diclofenac gel;5-fluorouracyl, bleaching agents and photoprotectors, and the like. Atherapeutic agent includes pharmaceutically acceptable salts thereof,prodrugs and pharmaceutical derivatives thereof.

In a first aspect, the present invention relates to the use of acompound of Formula (I) or a pharmaceutically acceptable salt orsolvate, isomer or prodrug thereof to prepare a drug for the cosmetic,therapeutic and/or prophylactic treatment of dermatitis or seborrheickeratosis, wherein the compound of the Formula (I) is:

wherein:

-   -   R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Z;    -   Y is —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃;    -   Z is —SO₃H, —SO₃ ⁻.X⁺. —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃, —CO₂H,        —CO₂ ⁻.X⁺ or —CO₂R₃;    -   X⁺ is an organic cation or an inorganic cation, such that the        general charge of the compound is neutral;    -   R₉ and R_(9′) are independently selected from —OH and —OR₂,        wherein when R₉ and R_(9′) are both —OR₂, then said R₉ and        R_(9′) can be the same or different;    -   R₂ is a substituted or unsubstituted alkyl group, a substituted        or unsubstituted aryl group, a substituted or unsubstituted        arylalkyl group, a substituted or unsubstituted alkylsulfonyl        group, a substituted or unsubstituted arylsulfonyl group, a        substituted or unsubstituted alkylarylsulfonyl group, a        substituted or unsubstituted arylalkysulfonyl group, a        substituted or unsubstituted aryloxyalkyl group, a substituted        or unsubstituted alkylcarbonyl group or an arylcarbonyl group, a        carboxyl group, a substituted or unsubstituted alkoxycarbonyl        group, a substituted or unsubstituted carboxyalkyl group, in        particular —CH₂—COOH, or a substituted or unsubstituted alkoxy-        aryloxy- arylalkoxy- or alkylaryloxy-carbonylalkyl, in        particular —CH₂—COOR₃;    -   R₃ is a substituted or unsubstituted alkyl group or a        substituted or unsubstituted aryl group;    -   a is number selected from 0, 1, 2, 3, 4, 5 and 6;    -   p is an integer selected from 0, 1, 2, 3, 4, S and 6,        with the proviso that when Y is —SO₃H, —SO₃ ⁻.X⁺ or —SO₃R₃, then        R₉ and R_(9′) are independently selected from —OH and —OR₂,        wherein at least one of R₉ and R_(9′) is a substituted or        unsubstituted alkylsulfonyloxy group, a substituted or        unsubstituted arylsulfonyloxy group, a substituted or        unsubstituted alkylcarbonyloxy group or a substituted or        unsubstituted arylcarbonyloxy group.

In a particular embodiment, 2,5-dihydroxybenzene derivatives of theinvention or any of the pharmaceutically acceptable salts thereof arethose that are represented by Formula (I) comprising dobesilate esterderivatives and the pharmaceutically acceptable salts thereof for thetreatment of dermatitis.

More particularly, the dermatitis is selected from the group consistingof actinic dermatitis, allergic contact dermatitis, atopic dermatitis,carcinomatous dermatitis, contact dermatitis, diaper dermatitis, stasisdermatitis, neurodermatitis, dermatomyositis and radiation-induceddermatitis.

The X⁺ cation in the compound of Formula (I) may be any physiologicallyacceptable cation known in the art, that includes but is not limited tothose described in P. Heinrich Stahl, Camille G. Wermuth (eds.),“Handbook of Pharmaceutical Salts Properties, Selections and Use”,Verlag Helvetica Chimica Acta, Zurich, Switzerland, Wiley-VCH, Weinheim,Germany, 2002.

The X⁺ cation is typically selected in such a way that the generalcharge of Formula (I) is neutral.

In a particular embodiment of the invention R1 is —(CH₂)_(a)Y or—CH═CH—(CH₂)_(p)Y. More particularly, Y is selected from —SO₃H, —SO₃⁻.X⁺, and —SO₃R₃.

In another particular embodiment of the invention, R₃ is selected frommethyl, ethyl, isopropyl or C₆H₅—, more preferably from methyl andethyl.

In another particular embodiment, R₁ is —(CH₂)_(a)Y or—CH═CH—(CH₂)_(p)Y.

In another particular embodiment, at least one of R₉ and R_(9′) are,independently, a substituted or unsubstituted alkylsulfonyloxy group, asubstituted or unsubstituted arylsulfonyloxy group, a substituted orunsubstituted alkylcarbonyloxy group or a substituted or unsubstitutedarylcarbonyloxy group.

In another particular embodiment. R₂ is selected from methylcarbonyl,phenylsulfonyl, 4-methylphenylsulfonyl, benzylsulfonyl, benzyl andphenyl

In another particular embodiment, R₂ is selected from methylcarbonyl,phenylsulfonyl, 4-methylphenylsulfonyl, benzylsulfonyl, benzyl andphenyl.

In another particular embodiment of the invention, R₂ is selected fromacetyl (—C(O)CH₃), tosyl (—SO₂—C₆H₄—CH₃) or p-chlorophenoxyisobutyryl(—C(O)—C(CH₃)₂—O—C6H₄Cl).

In a preferred embodiment of the invention, the inorganic cation issodium, potassium, lithium, calcium, or magnesium.

In another preferred embodiment of the invention, the organic cation is[NH_(4-p)R_(p)]⁺: wherein p is an integer between 0 and 4 and R is analkyl group having one to six carbon atoms such as, for example, methyl,ethyl, n-propyl, i-propyl, t-butyl or n-pentyl.

In another preferred embodiment of the invention, the organic cation isthe diethylamine [H₂N⁺(C₂H₅)₂], piperazine or pyridine group.

In another preferred embodiment of the invention, the compound ofFormula (I) and acceptable salts thereof are:

wherein:

n is a number selected from 1 and 2;

m is a number selected from 1 and 2; and

X, R₂ and R₃ are as defined in the present invention.

In a more preferred embodiment of the invention, the compound of FormulaI is:

-   5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2,5-bis{4[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2-(acetyloxy)-5-hydroxybenzenesulfonic acid;-   5-(acetyloxy)-2-hydroxybenzenesulfonic acid;-   2,5-bis(acetyloxy)benzenesulfonic acid;-   5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;-   2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;-   2,5-bis{([(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;-   2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;-   5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;-   2,5-bis(acetyloxy)benzenehomosulfonic acid;-   3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic    acid);-   3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic    acid;-   3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic    acid;-   3-(2,5-bis {[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;-   3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid;-   3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;-   3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;-   3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;-   3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;-   3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid;

and pharmaceutically acceptable salts, solvates and prodrugs thereof.

Particularly preferred are the compounds2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid and2,5-bis(acetyloxy)benzenesulfonic acid.

2,5-dihydroxybenzene derivatives may be optionally used combined witheach other. In this manner and as an example, it is possible to combinea dobesilate ester derivative with a homodobesilate ester derivative,and the like in the same or in a different ratio. Said combinations maybe in the same formulation or in formulations that would be usedsequentially.

The compounds of Formula (I) may be synthesized by one skilled in theart using conventional and commercially available methods. The synthesisof the compounds of Formula (I) is disclosed in, for example, U.S. Pat.No. 5,082,941; and “The Merck Index” 13th. edition, Merck & Co., R.Railway, N.J., USA, 2001; U.S. Pat. Nos. 5,082,841, 4,814,110, 4,613,332and 4,115,648; the disclosures which are incorporated herein byreference in their entirety.

Compounds of Formula (I) also may be in the form of solvates,particularly in the form of hydrates. The preparation of the compoundsof Formula (I), as well as the solvates thereof may be carried out byone skilled in the art using conventional methods and commerciallyavailable reagents.

Even as it has been previously mentioned in one of the preferredembodiments with respect to the definition of X⁺ cation, the scope ofthe present invention encompasses any salt thereof, especially anypharmaceutically acceptable salt of the compound. The phrase“pharmaceutically acceptable salts” includes metal salts or the additionsalts that may be used in pharmaceutical forms. For example, thepharmaceutically acceptable salts of the compounds provided herein maybe acid addition salts, base addition salts or metal salts and they maybe synthesized from the parenteral compounds containing a base or acidresidue using conventional chemical processes. Generally, those saltsare prepared, for example, by the reaction of free base or acid forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water or in an organic solvent, or in a mixture of both.Generally, non aqueous mediums such as ether, ethyl acetate, ethanol,isopropanol or acetonitrile are preferred. The examples of acid additionsalts include addition salts of mineral acids such as, for example,hydrochloride, bromohydrate, iodide hydrate, sulfate, nitrate,phosphate, addition salts of organic acids such as, for example,acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate,malate, mandelate, methanesulfonate and p-toluenesulfonate. The examplesof alkali addition salts include inorganic salts such as, for example,ammonium salts and organic alkaline salts such as, for example,diethylamine, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine,triethanolamine, glutamine and basic amino acid salts. The examples ofmetal salts include, for example, sodium, potassium, calcium, magnesium,aluminum, and lithium salts.

In some embodiments, the invention provides a composition comprising anester derivative of a compound of Formula (I), especially an dobesilateester derivative, such as 2-acetyloxy-5-hydroxybenzenesulfonic acid,5-acetyloxy-2-hydroxybenzenesulfonic acid, or2,5-bis-acetyloxybenzenesulfonic acid. In some embodiments, it will bedesirable to formulate a composition of the invention with an activeprinciple such as a dobesilate ester derivative, for example, whereinthe ester derivative shows more therapeutic efficacy than the originalcompound in the treatment or prevention of a condition described herein.In other embodiments, the invention includes the use of a dobesilateester derivative as a prodrug, for example, to treat a conditiondescribed herein, wherein the ester derivative is metabolized to theoriginal compound in a patient to achieve therapeutic efficacy in thepatient.

The phrase “pharmaceutically acceptable” refers to physiologicallytolerable molecular entities and compositions which do not typicallyproduce an allergic or similar adverse reaction, such as gastric upset,dizziness, and the like, when administered to a human. Preferably, asused herein, the term “pharmaceutically acceptable” means that it isapproved by a regulatory agent of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopoeia as suitable for use in animals, and more particularly, inhumans.

It would be obvious to those skilled in the art that the scope of thepresent invention also encompasses salts that are not pharmaceuticallyacceptable as possible media to obtain pharmaceutically acceptablesalts.

As used herein, the term “solvate” shall refer to any form of the activecompound according to the invention that exhibits another molecule (mostprobably, a polar solvent) bound to it through a non-covalent bond.Examples of solvates include hydrates and alcoholates, preferably, C₁-C₆alcoholates, for example, methanolate.

The pharmaceutically acceptable salts of Formula (I) may be preparedfrom organic or inorganic acids or basis by conventional methods throughthe reaction of the appropriate acid or base with the compound.

In a particular embodiment, 2,5-dihydroxybenzenic derivatives of theinvention may be used optionally and jointly with at least one of thefollowing therapeutic agents: diclofenac, T4 endonuclease, isotretinoin,acitretin, cidofoir, a corticosteroid, an antibiotic, an analgesic, animmunomodulator, including oral immunomodulator such as tacrolimus andpimecrolimus, and topical immunomodulators; an immunosuppressant, ananti-angiogenic, including anti-VEGF, anti-FGF, anti-EGF and anti-HGF; aleukotriene modifier, an aminosalicylate, an anesthetic, a non-steroidalanti-inflammatory, a therapy of the solubilized interleukin receptor,inhibitors of tyrosin-kinase receptors, protein kinase C inhibitors, andcombinations of two or more thereof.

A medicament comprising a compound of formula (I) of the invention maybe presented in any suitable form for administration, for example, forsystemic, transdermal, oral, parenteral, buccal, nasal (e.g., byinhalation), topical, rectal, intravaginal, intraocular or opticaladministration; therefore, a medicament of the invention may include theacceptable pharmaceutical excipients or vehicles necessary to beformulated in the desired form of administration. In a preferredembodiment, the pharmaceutical composition is administered topically.

Thus, in one preferred aspect, the present invention refers to a methodfor the treatment and/or prophylaxis of dermatitis in a patient in needof the treatment and it comprises the administration to the patient ofan effective amount of the described compounds and/or compositions ofFormula (I).

The compounds of formula (I) may be optionally administered togetherwith at least one therapeutic agent, such as, diclofenac, T4endonuclease, isotretinoin, acitretin, cidofoir, a corticosteroid, anantibiotic, an analgesic, an immunomodulator, including oralimmunomodulator such as tacrolimus and pimecrolimus, and topicalimmunomodulators; an immunosuppressant, an anti-angiogenic, includinganti-VEGF, anti-FGF, anti-EGF and anti-HGF; a leukotriene modifier, anaminosalicylate, an anesthetic, a non-steroidal anti-inflammatory, atherapy of the solubilized interleukin receptor, inhibitors oftyrosin-kinase receptors, protein kinase C inhibitors, and combinationsof two or more thereof.

In other embodiments, the application of the 2,5-dihydroxybenzenecompounds represented by Formula (I) may be made independently or, in apreferred aspect, simultaneously with the use of equivalent or differentmixes of other 2,5-dihydroxybenzene compounds represented by Formula (I)(including pharmaceutically acceptable salts and esters) and thesecompounds may be in the same formulation or in independent formulationsthat would be simultaneously or sequentially administered.

In another aspect, the present invention refers to a cosmetic productcomprising 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I).

In an embodiment, the present invention refers to a cosmetic productthat comprises 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I)characterized in that the compound of Formula (I) is an ester derivativeof 2,5-dihydroxybenzenesulfonic acid or pharmaceutically acceptablesalts or esters thereof.

In another embodiment, the present invention refers to a cosmeticproduct that comprises 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I)characterized in that the compound of Formula (I) is an ester derivativeof 2,5-dihydroxybenzene homosulfonic acid or pharmaceutically acceptablesalts or esters thereof.

In another embodiment, the present invention refers to a cosmeticproduct characterized in that the compound of Formula (I) is an esterderivative of 2,5-dihydroxybenzenesulfonic acid or the pharmaceuticallyacceptable salts or esters thereof characterized in that it consists ofa formulation for dermatitis or seborrheic keratosis.

In another embodiment, the present invention refers to a cosmeticproduct according to any of the previous aspects characterized in thatit is presented in the form of cream, ointment, unguent, microsomes,bandages, or patches.

In another embodiment, the present invention refers to a cosmeticproduct according to any of the previous aspects characterized in thatit contains an amount of 5% of an ester derivative of2,5-dihydroxybenzene sulfonic acid.

In another embodiment, the present invention refers to a cosmeticproduct according to any of the previous aspects characterized in thatit comprises as excipients: cetyl alcohol (2.5%), stearyl alcohol(2.5%), liquid vaseline (30%), filante vaseline (20%), sorbitanmonooleate (5%) and distilled water (q.s. to 100 g).

In another embodiment, the present invention refers to the use of2,5-dihydroxybenzene derivatives or any of the pharmaceuticallyacceptable esters or salts thereof represented by Formula (I) to preparea formulation intended to be cosmetically used.

In another embodiment, the present invention refers to a method forcosmetic or therapeutic treatment of dermatitis, comprising theadministration to a patient of a composition comprising a compound ofFormula (I).

In one embodiment, the present invention refers to the use of2,5-dihydroxybenzene derivatives or any pharmaceutically acceptableesters or salts thereof represented by Formula (I) wherein the compoundof Formula (I) is an ester derivative of 2,5-dihydroxybenzenesulfonicacid or the salts or esters thereof, to prepare a drug or medicineintended for the cosmetic or therapeutic treatment of dermatitis.

In one embodiment, the present invention refers to the use of2,5-dihydroxybenzene derivatives or any pharmaceutically acceptableesters or salts thereof represented by Formula (I) wherein the compoundof Formula (I) is an ester derivative of 2,5-dihydroxybenzenehomosulfonic acid or the salts and esters thereof, to prepare a drug ormedicine intended for the cosmetic or therapeutic treatment ofdermatitis.

Another aspect of the present invention refers to a method for thecosmetic treatment of any of the diseases comprised in the followinggroup: seborrheic keratosis, atopic dermatitis or contact dermatitis,comprising the administration to a patient of a composition comprisingFormula (I), or the pharmaceutically acceptable salts or esters thereof.

Another aspect of the present invention refers to a method fortherapeutic treatment of dermatitis, comprising the administration to apatient of a composition comprising Formula (I), or the pharmaceuticallyacceptable salts or esters thereof.

The duration of treatment will typically depend on the particularcondition, its severity, the condition of the patient, and the like, andwill readily be determined by one of skill in the art. Illustrativecourses of therapy include 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3.5months, 4 months, 4.5 months, 5 months, 6 months, 9 months, a year, orlonger as needed.

In treating a subject suffering from a disorder described herein,treatment may be continued until at least a 10% improvement is effectedin a symptom associated with the condition. In other embodiments,treatment is continued until the subject in need of such treatmentexperiences an improvement of at least about 20%, at least about 30%, atleast about 40%, preferably at least about 50%, preferably at leastabout 60%, more preferably at least about 70%, more preferably at leastabout 80%, even more preferably 90% or greater in a symptom associatedwith a disorder described herein.

In a particular embodiment of the invention, a compound of formula (I)is administered at least once per week. In other embodiments, a compoundof formula (I) is administered at least once per day. In yet otherembodiments, a compound of formula (I) is administered twice per day. Inanother particular embodiment, a compound of formula (I) is administeredover a period of at least about one week. In other embodiments, acompound of formula (I) is administered over a period of at least aboutfour weeks.

Therapeutic amounts can be empirically determined and will vary with theparticular condition being treated, the subject, the particularformulation components, dosage form, and the like.

In a particular embodiment, a compound of formula (I) is present in apharmaceutical composition in an amount of at least about 1% w/w. Inother embodiments, a compound of formula (I) is present in apharmaceutical composition in an amount of at least about 2.5% w/w, atleast about 5% w/w, at least about 10% w/w, or at least about 15% w/w.

In another particular embodiment of the invention, the inventive2,5-dihydroxybenzene compounds of Formula (I) may be administeredtopically in a formulation comprising from about 0.001% to about 30%(w/w) of the inventive 2,5-dihydroxybenzene compounds of Formula (I). Ina preferred aspect of the invention, the inventive 2,5-dihydroxybenzenecompounds of Formula (I) may be administered topically in a formulationcomprising from about 0.01% to about 20% (w/w) of the inventive2,5-dihydroxybenzene compounds of Formula (I). In another preferredaspect of the invention, the inventive 2,5-dihydroxybenzene compounds ofFormula (I) may be administered topically in a formulation comprisingfrom about 0.1% to about 15% (w/w) of the inventive 2,5-dihydroxybenzenecompounds of Formula (I). In a preferred aspect of the invention, theinventive 2,5-dihydroxybenzene compounds of Formula (I) may beadministered topically in a formulation comprising from about 0.5% toabout 10% (w/w) of the inventive 2,5-dihydroxybenzene compounds ofFormula (I). In another preferred aspect of the invention, the inventive2,5-dihydroxybenzene compounds of Formula (I) may be administeredtopically in a formulation comprising from about 1% to about 5% (w/w) ofthe inventive 2,5-dihydroxybenzene compounds of Formula (I). In anotherpreferred aspect of the invention, the inventive 2,5-dihydroxybenzenederivatives: of Formula (I) may be administered topically in aformulation comprising from about 2.5% to about 4% (w/w) of theinventive 2,5-dihydroxybenzene compounds of Formula (I). The topicformulation of the compounds comprised in the inventive2,5-dihydroxybenzene compounds: of Formula (I) may be administered as asingle dose once a day or in multiple doses several times a day. In apreferred aspect of the invention, the topical formulation whichcomprises 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of theinventive 2,5 dihydroxybenzene compounds of Formula (I), is administeredfour times a day. In another preferred aspect of the invention, thetopical formulation which comprises about 30%, 20%, 15%, 10%, 5%, 2.5%,1%, 0.5%, 0.1% or 0.001% of the inventive 2,5 dihydroxybenzene compoundsof Formula (I), is administered three times a day. In another preferredaspect of the invention, the topical formulation which comprises about30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the inventive2,5 dihydroxybenzene compounds of Formula (I), is administered twice aday. In another preferred aspect of the invention, the topicalformulation which comprises about 30%, 20%, 15%, 10%, 5%, 2.5%, 1%,0.5%, 0.1% or 0.001% of the inventive 2,5 dihydroxybenzene compounds ofFormula (I), is administered once a day.

Topical Compositions

The product of the present invention is useful for topical applicationon the skin. The compositions comprise an effective amount of theinventive compounds: of Formula (I), preferably from about 0.001 to 30%.Furthermore, the composition comprises a pharmaceutical acceptablevehicle. The appropriate vehicles remain in the place of application onthe skin forming a continuous film resistant to water immersion andperspiration. Generally, the vehicle is organic and capable ofcontaining the formulation of the invention in a diluted or dispersedform. Lotions, creams, solutions, gels and solids are the usual physicalforms of the composition.

Topical application means depositing or spreading the compound and thecompositions over the epidermic tissue (including skin and oral,gingival, nasal, etc. tissues).

Lotions

Lotions contain from about 0.001% to about 30% of the inventivecompounds of Formula: (I) from 1% to 25% of an emollient and theappropriate amount of water. Examples of emollients are:

-   -   I. Hydrocarbon waxes and oils such as mineral oils, petrolatum,        paraffin, ceresin, microcrystalline wax, polyethylene and        perhydrosqualene.    -   II. Silicone oils such as dimethylpolysiloxanes,        methylphenylpolysiloxanes and water-soluble and alcohol-soluble        glycol-silicone copolymers.    -   III. Triglycerides, such as animal and vegetable fats and oils.        Examples include, but are not limited to, castor oil, cod liver        oil, corn oil, olive oil, almond oil, palm oil, sesame oil,        cotton seed oil and soybean oil.    -   IV. Acetoglyceride esters, such as acetylated monoglycerides.    -   V. Ethoxylated glycerides, such as ethoxylated glycerol        monostearate.    -   VI. Alkyl esters of fatty acids having 10 to 20 carbon atoms.        Methyl, isopropyl and butyl esters of fatty acids are useful        herein. Examples include, but are not limited to, hexyl laurate,        isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl        oleate, isodecyl oleate, hexadecyl stearate, decyl stearate,        isopropyl isostearate, diisopropyl adipate, diisohexyl adipate,        dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate,        myristoyl lactate and cetyl lactate.    -   VII. Alkenyl esters of fatty acids having 10 to 20 carbon atoms.        Examples thereof include, but are not limited to, oleyl        myristate, oleyl stearate and oleyl oleate.    -   VIII. Fatty acids having 10 to 20 carbon atoms. Suitable        examples include, but are not limited to, pelargonic, lauric,        myristic, palmitic, stearic, isostearic, hydroxystearic, oleic,        linoleic, ricinoleic, arachidonic, behenic and erucic acids.    -   IX. Fatty alcohols having 10 to 20 carbon atoms. Lauryl,        myristoyl, palmitoyl, stearyl, isostearyl, hydroxystearyl,        oleyl, ricinoleyl, behenyl, erucyl and 2-octyl dodecanol        alcohols are appropriate examples of fatty alcohols.    -   X. Fatty alcohol ethers. Ethoxylated fatty alcohols having 10 to        20 carbon atoms include, but are not limited to, lauryl, cetyl,        stearyl, isostearyl, oleyl and cholesterol alcohols having        attached thereto from 1 to 50 ethylene oxide groups or 1 to 50        propylene oxide groups.    -   XI. Ether-esters, such as fatty acid esters of ethoxylated fatty        alcohols.    -   XII. Lanolin and derivatives. Lanolin, lanolin oil, lanolin wax,        lanolin alcohols, lanolin fatty acids, isopropyl lanolate,        ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated        cholesterol, propoxylated lanolin alcohols, acetylated lanolin,        acetylated lanolin alcohols, lanolin alcohols linoleates,        lanolin alcohols ricinoleate, acetate of lanolin alcohols        ricinoleate, hydrogenolysis of lanolin, and liquid or semisolid        lanolin absorption bases are illustrative examples of lanolin        derived emollients.    -   XIII. Polyhydric alcohols and polyether derivatives. Propylene        glycol, dipropylene glycol, polypropylene glycol 2000 and 4000,        polyoxyethylene polypropylene glycols, glycerol, ethoxylated        glycerol, propoxylated glycerol, sorbitol, ethoxylated sorbitol,        hydroxypropyl sorbitol, polyethylene glycol 200-6000, methoxy        polyethylene glycols 350, 550, 750, 2000, 5000, poly(ethylene        oxide) homopolymers (100,000-5,000,000), polyalkylene glycols        and derivatives, hexylene glycol (2-methyl-2,4-pentanediol),        1,3-butylene glycol, 1,2,6-hexanetriol, ethohexadiol USP        (2-ethyl-1,3-hexanediol), and polyoxypropylene derivatives of        trimethylolpropane are suitable examples.    -   XIV. Polyhydric alcohol esters. Mono- and di-acyl esters of        ethylene glycol, mono- and di-acyl esters of diethylene glycol,        mono- and di-acyl esters of polyethylene glycol (200-6000),        mono- and di-acyl esters of propylene glycol, polypropylene        glycol 2000 monooleate, polypropylene glycol 2000 monostearate,        ethoxylated propylene glycol monostearate, mono- and di-acyl        esters of glycerol, poly-acyl esters of poly glycerol,        ethoxylated glycerol monostearate, 1,3-butylene glycol        monostearate, 1,3-butylene glycol distearate, acyl ester of        polyoxyethylene polyol, acyl esters of sorbitan, and acyl esters        of polyoxyethylene sorbitan are suitable examples.    -   XV. Waxes such as beeswax, spermaceti, myristoyl myristate and        stearyl stearate.    -   XVI. Beeswax derivatives, such as polyoxyethylene sorbitol        beeswax. These are reaction products of beeswax with ethoxylated        sorbitol of varying ethylene oxide content that form a mixture        of ether-esters.    -   XVII. Vegetable waxes, including, but not limited to, carnauba        and candelilla waxes.    -   XVIII. Phospholipids such as lecithin and derivatives.    -   XIX. Sterols. Examples include, but are not limited to,        cholesterol and acyl esters of cholesterol.    -   XX. Amides, such as fatty acid amides, ethoxylated acyl amides        and solid fatty acid alkanolamides.

The lotions of the invention would further contain from 1% to 30% of anemulsifier. The emulsifiers can be anionic, cationic or non-ionic.Examples of non-ionic emulsifiers include, but are not limited to, fattyalcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20carbon atoms condensed with 2 to 20 moles of ethylene oxide or propyleneoxide, alkyl phenols with 6 to 12 carbons in the alkyl chain condensedwith 2 to 20 moles of ethylene oxide, mono- and di-acyl esters ofethylene glycol, wherein the fatty acid contains from 10 to 20 carbons,monoglycerides wherein the fatty acid contains from 10 to 20 carbons,diethylene glycol, polyethylene glycols of molecular weight 200 to 6000,polypropylene glycol of molecular weight 200 to 3000, glycerol,sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitanand hydrophilic wax esters. Suitable anionic emulsifiers include, butare not limited to, fatty acids saponified (soaps) with potassium,sodium, or triethanolamine, wherein the fatty acid contains from 10 to20 carbons. Other suitable anionic emulsifiers include, but are notlimited to, alkali metals, ammonium or substituted ammonium with alkylsulfates, alkyl arylsulfonates and alkyl ethoxy ether sulfonates having10 to 30 carbons in the alkyl chain and from 1 to 50 ethylene oxideunits. Suitable cationic emulsifiers include quaternary ammonium andmorpholinium and pyridinium compounds.

Some emollients previously described also have emulsifying properties.When a lotion contains one of these emollients, an additional emulsifieris not needed, though it can be included in the formulation.

The balance of the composition is water. The lotions are formulated bysimply admixing all of the components together. Preferably, thecompounds of Formula I are dissolved in the emollient and the resultingmixture is added into the water. Optional components such as theemulsifier or common additives may be included in the composition. Acommon additive is a thickening agent included at a level of 1% to 30%by weight of the composition. Examples of suitable thickening agentsare: Cross-linked carboxypolymethylene polymers, methyl cellulose,polyethylene glycols, gums and bentonite.

Creams

The compositions of the present invention may be also formulated in theform of a cream. Creams contain from 0.001% to 30% of the inventivecompounds of Formula (I), from 5% to 50% of an emollient and theremainder is water. The emollients, as described above, can also be usedin the cream formulation. Optionally, the cream may contain anemulsifier at a level from 3% to 50%. The previously describedemulsifiers would also be adequate in this case.

Solutions

The compositions of the present invention may also be formulated in theform of a solution. Solutions contain from 0.001% to 30% of theinventive compounds: of Formula (I), and the adequate amount of anorganic solvent. Organic substances useful as the solvent or a part ofthe solvent system are as follows: propylene glycol, polyethylene glycol(200-600), polypropylene glycol (425-2025), glycerine, sorbitol esters,1,2,6-hexanetriol, ethanol, isopropanol, diethyl tartrate, butanediol,and mixtures thereof. Such solvent systems can also contain water. Thesecompositions are applied on the skin in the form of a solution, orsolutions are formulated in the form of aerosol and applied on the skinas a spray. Compositions in the form of aerosol additionally containfrom 25% to 80% of a suitable propellant. Examples of propellantsinclude, but are not limited to: chlorinated, fluorinated andfluorochlorinated low molecular weight hydrocarbons. Nitrous oxide andcarbon dioxide are also used as propellant gases. Enough quantity toexpel the content of the cartridge is used.

Gels

The composition in the form of gel might be simply obtained by theaddition of a suitable thickening agent to the composition in the formof a solution as described above. Suitable thickening agents have beendescribed in the chapter referring to lotions.

Gel formulations contain from about 0.001% to about 30% of the compoundsof Formula (I), 5% to 75% of a suitable organic solvent, 0.5% to 20% ofa suitable thickening agent and the required amount of water.

Solids

The compositions in the present invention may also be formulated insolid form. Such forms have the shape of a bar intended for theapplication on the lips or other parts of the body. These compositionscontain from about 0.001% to about 30% of the inventive compounds: ofFormula (I), and from about 50% to about 98% of an emollient such as theone already described. The composition may be further contain from about1% to about 20% of a suitable thickening agent, such as those alreadydescribed, and, optionally, emulsifiers and water.

Additives usually found in topical compositions, such as preservatives(for example, methyl and ethyl paraben), dyes and perfumes may beincluded in any of the formulations described herein.

Application Method

The effective amount of compounds of Formula (I) used topically willvary according to the specific circumstances of application, theduration of exposure and similar considerations. Generally, the amountwill vary from 0.01 microgram to 50 milligrams of the compounds ofFormula (I), per square centimeter of the epidermis area. The amount oftopical composition (the compounds of Formula (I) and the vehicle)applied on the affected area may be easily determined according to theamount of compounds of Formula (I) contained therein.

Kits

In yet other embodiments, the invention provides a kit or packagecomprising a compound of formula (I), in packaged form, accompanied byinstructions for use. The compound of formula (I) may be packaged in anymanner suitable for administration, so long as the packaging, whenconsidered along with the instructions for administration, indicates themanner in which the compound of formula (I) is to be administered.

For example, a kit may comprise a compound of formula (I) in unit dosageform, along with instructions for use. For example, such instructionsmay indicate that administration of a compound of formula (I) is usefulin the treatment of dermatitis. The compound of formula (I) may bepackaged in any manner suitable for administration. For example, whenthe compound of formula (I) is in oral dosage form, e.g., is in the formof a coated tablet, then the kit may comprise a sealed container ofcoated tablets, blister strips containing the tablets, or the like.

Various embodiments according to the above may be readily envisioned,and would depend upon the particular dosage form, recommended dosage,intended patient population, and the like. The packaging may be in anyform commonly employed for the packaging of pharmaceuticals, and mayutilize any of a number of features such as different colors, wrapping,tamper-resistant packaging, blister packs or strips, and the like.

The following non-limiting examples further describe and enable one ofordinary skill in the art to make and use the present invention.

EXAMPLES Example 1: Effect of 2,5-dihydroxybenzenesulfonate and theEster Thereof, 2,5-diacetoxybenzenesulfonate on Dermatitis

Dermatitis was induced by the application of benzalkonium chloride, 5%solution (w/v) (1:5 olive oil:acetone) on the entire extent of the backpart of the car (40 L/ear) in anesthetized rats. Dermatitis was inducedin both ears. In the assay of 2,5-dihydroxybenzenesulfonate (DHBS), acream containing 5% of DHBS (w/w) was applied topically only on the backpart of the right ear, 30 minutes after the application of benzalkoniumchloride. Fifteen minutes later, 0.5% by weight of Evans blue dyesolution (400 μL per animal) was injected into the jugular vein. Thisdye only stains in blue the areas of the skin that exhibit an alterationof the vascular permeability which enables the extravasation of the dye,as would correspond to a dermatitis process. Four hours after inducingdermatitis in both cars, the left car of the studied rats (n=6) whichhad not been treated, exhibited a vast and intense blue stain, as shownin FIG. 1. Nevertheless, the right ear of all the rats treated with 5%DHBS exhibited a clearly smaller blue stain than the one in therespective left ear of each case (FIG. 1). Therefore, it can be statedthat topical application of 5% DHBS reduced the dermatitis extent.

This observation was confirmed upon quantification of dermatitis extentbased on the area of the ear stained in blue with respect to the totalarea of the ear. Identically obtained photographs of the extended earswere processed in order to determine the stained area and the total areaof the ear using a computer program to analyze images (Motic Image). Thestained area of each ear was related to the total area to obtain thepercentage of the ear affected by the dermatitis. The statistic analysisof the resulting values, 4 hours after the application of benzalkoniumchloride on the treated and untreated ears, revealed that the treatmentwith cream containing DHBS at 5% by weight significantly reduced thepercentage of the area stained in blue, as shown in FIG. 2A, thus,showing an inhibitory effect of DHBS on the development of dermatitis.24 hours after dermatitis induction (FIG. 2B), these values were verysimilar.

Using the same model, dermatitis was induced on both ears of two rats,following the same process described above. In this case, 30 minutesafter the application of benzalkonium chloride, a rat was treated inboth ears with a glycerol solution (FIG. 3A), while the other one wastreated in both ears with a glycerol solution containing 2.5% (w/v) of2,5-diacetoxybenzenesulfonate (DABS) (FIG. 3B). The topical treatmentwith DABS reduced benzalkonium chloride induced dermatitis, as evidencedby the fact that the ears of the rats treated with the vehicle(glycerol) exhibit a much more intense erythema than that correspondingto the rats treated with DABS. The histological study of these earsevidences that the topical treatment with 2.5% of DABS reduces the edemaand the leukocyte infiltration (FIG. 4). The ears treated with DABS showa significant reduction of the presence of granulocytes adhered to thecapillary endothelial cells, in its step previous to extravasationtowards the subjacent tissue (FIGS. 4e and 4f ).

In this same model (Hyun E et al. Br J Pharmacol, 2004), dermatitisinduction has been associated to an increase in the myeloperoxidase(MPO) activity in the ear, as a marker of leukocyte infiltration in thetissue affected with dermatitis. Based on these evidences, the effect ofhydroxybenzene derivatives (i the activity of the MPO in the modeldescribed in this example was established. The MPO activity wasdetermined in the ears of control rats (without dermatitis) and in earson which dermatitis had been induced with benzalkonium chloride and hadbeen treated with vehicle (anhydrous glycerol), 5% DHBS cream or DABS2.5% solution in glycerol. The ears were frozen in liquid nitrogen 24hours after the induction of dermatitis and were kept at −80° C. untildetermination of MPO activity. To determine the MPO activity, the frozenears were homogenized in phosphate buffer with 0.5% ofhexadecyltrimethylammonium bromide. After severalfreezing/thawing/sonication cycles, the samples were centrifuged at13,000×g during 20 minutes at 4° C. H₂O₂ and O-dianisidine were addedinto the supernatants and the absorbance was measured at 460 nm in aspectrophotometer 1 hour after incubation at room temperature. The MPOactivity is expressed as absorbance units per mg of tissue.

24 hours later, the dermatitis produces a significant increase in theMPO activity in the ear which is significantly reduced by the topicaltreatment with 5% DHBS (FIG. 5). The topical application of 2.5% of DABSalso significantly reduces the increase of MPO activity caused by thedermatitis. In fact, when the DABS topical formulation contained half ofthe amount of active principle contained in the DHBS, its efficacy wasslightly higher (FIG. 5).

This example shows the efficacy of the topical application of DHBS andof the diacetylated form thereof, DABS, for the treatment of dermatitisin an animal model.

As the foregoing example illustrates, in certain embodiments, the estersof 2,5-dihydroxybenzene sulfonate described in the present inventionsurprisingly exert pharmacological actions of interest in the presentinvention by themselves, without needing to be first converted into2,5-dihydroxybenzenesulfonate in order to exert such actions.

Example 2: Effect of Monoesters of 2,5-dihydroxybenzenesulfonate onDermatitis

Using the same procedure as in the former example, dermatitis wasinduced by the application of benzalkonium chloride, 5% solution (w/v)(1:5 olive oil:acetone) on the entire extent of the back part of the ear(40 μL/ear) in anesthetized rats. Dermatitis was induced in both ears. Acream containing 5% (w/v) of either 2-acetoxy-5-hydroxybenzenesulfonate(2A-5HBS) or 5-acetoxy-2-hydroxybenzenesulfonate (5A-2HBS) was appliedtopically only on the back part of the right ear, 30 minutes after theapplication of benzalkonium chloride. Fifteen minutes later, 0.5% (w/v)of Evans blue dye solution (400 μL per animal) was injected into thejugular vein. This dye only stains in blue the areas of the skin thatexhibit an alteration of the vascular permeability which enables theextravasation of the dye, as would correspond to a dermatitis process.Twenty four hours after inducing dermatitis in both ears, the left earof the studied rats (n=5) which had not been treated, exhibited a vastand intense blue stain, as shown in FIG. 6. Nevertheless, the right earof all the rats treated with 5% 2A-5HBS exhibited a clearly smaller bluestain than the one in the respective left ear of each case (FIG. 6). Inthe same way, rats treated with 5% 5A-2HBS presented marked blue stainin the left (untreated) ears while the extent of the staining in theright (treated) ears was notably reduced (FIG. 7). Therefore, it can bestated that topical application of 5% 2A-5HBS and 5% 5A-2HBS reduced thedermatitis extent.

This observation was confirmed upon quantification of dermatitis extentbased on the area of the ear stained in blue with respect to the totalarea of the ear. Identically obtained photographs of the extended earswere processed in order to determine the stained area and the total areaof the ear using a computer program to analyze images (Motic Image). Thestained area of each car was related to the total area to obtain thepercentage of the ear affected by the dermatitis. The statistic analysisof the resulting values, 24 hours after the application of benzalkoniumchloride on the treated and untreated cars, revealed that the treatmentwith 2A-5HBS solution at 5% by weight significantly reduced thepercentage of the area stained in blue, as shown in FIG. 8, as well asdid it the treatment with 5% (w/v) 5A-2HBS solution (FIG. 9) thus,showing an inhibitory effect of the monoesters of2,5-dihydroxybenzenesulfonate at positions 2 (2A-5HBS) or 5 (5A-2HBS) onthe development of dermatitis.

Example 3: Analysis of the Structural Interaction of the Esters of2,5-dihydroxybenzenesulfonate with the Fibroblast Growth Factor-1(FGF-1)

As of the diffraction from complex crystals of FGF-1:2-acetoxy-5-hydroxybenzenesulfonic acid, FGF-1;5-acetoxy-2-hydroxybenzenesulfonic acid and FGF-1:2,5-diacetoxybenzenesulfonic acid, the complex structures werecalculated and represented. In FIGS. 10, 11 and 12, representing thesurface of the protein coloured according to its electrostatic potential(light grey: negative charge, dark grey: positive charge, white: areaswith no charge), the interaction form of the2-acetoxy-5-hydroxybenzenesulfonic acid,5-acetoxy-2-hydroxybenzenesulfonic acid and 2,5-diacetoxybenzenesulfonicacid, respectively, with the FGF-1 may be observed. The electronicdensity of the compound, contoured at to (FIGS. 10-12, panels C),enabled the localization and determination of the orientations of thecompounds regarding the protein (FIGS. 10-12, panels A and B), as wellas the confirmation that the compounds keep the acetoxyl groups inpositions 2, 5 and, 2 and 5, respectively, when they bind to theprotein. The compounds are located at a site very close to the sitethat, as described, is occupied by the 2,5-dihydroxybenzenesulfonicacid, which aromatic ring forms a cation-n bond with the N^(ε) group oflysine 132, marked in FIGS. 10-12, panels A, as reference.

Each patent, patent application, and publication cited or described inthe present application is hereby incorporated by reference in itsentirety as if each individual patent, patent application, orpublication was specifically and individually indicated to beincorporated by reference.

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. One skilledin the art will appreciate that numerous changes and modifications canbe made to the invention, and that such changes and modifications can bemade without departing from the spirit and scope of the invention. Thefull scope of the invention should be determined by reference to theclaims, along with their full scope of equivalents, and thespecification, along with such variations.

What is claimed is:
 1. A method for the treatment or prophylaxis ofseborrheic keratosis, comprising administering topically to a subject inneed thereof, an effective amount of a 2,5-dihydroxybenzene derivativerepresented by Formula (1) or a pharmaceutically acceptable salt, orsolvate thereof, wherein the compound of Formula (1) is:

wherein: R₁ is (CH₂)_(a)Y or CH═CH—(CH₂)_(p)Z; Y is —SO₃H, —SO₃ ⁻.X⁺,—SO₃R₃, —PO₃H, —PO₃—.X⁺, or —PO₃R₃, wherein when Y is —SO₃H, —SO₃ ⁻.X⁺or —SO₃R₃, then R₉ and R_(9′) are independently selected from —OH and—OR₂, wherein at least one of R₉ and R_(9′) is a substituted orunsubstituted alkylsulfonyloxy group, a substituted or unsubstitutedarylsulfonyloxy group, a substituted or unsubstituted arylsulfonyloxygroup, a substituted or unsubstituted alkylcarbonyloxy group or asubstituted or unsubstituted arylcarbonyloxy group; Z is —SO₃H, —SO₃⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃, —CO₂H, —CO₂ ⁻.X⁺ or —CO₂R₃; X⁺ isan organic cation or an inorganic cation, such that the general chargeof the compound is neutral; R₉ and R_(9′) are independently selectedfrom —OH and —OR₂, wherein when R₉ and R_(9′) are both —OR₂, then saidR₉ and R_(9′) can be the same or different; R₂ is a substituted orunsubstituted alkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted alkylsulfonyl group, a substituted orunsubstituted arylsulfonyl group, a substituted or unsubstitutedalkylcarbonyl group or a substituted or unsubstituted arylcarbonylgroup; R₃ is a substituted or unsubstituted alkyl group or a substitutedor unsubstituted aryl group; a is a number selected from 0, 1, 2, 3, 4,5 and 6; and p is an integer selected from 0, 1, 2, 3, 4, 5 and
 6. 2.The method of claim 1, wherein R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Y.3. The method of claim 2, wherein Y is selected from —SO₃H, —SO₃ ⁻.X⁺,—SO₃R₃.
 4. The method of claim 3, wherein R₃ is selected from methyl andethyl.
 5. The method of claim 1, wherein R₉ and R_(9′) are,independently, a substituted or unsubstituted alkylsulfonyloxy group, asubstituted or unsubstituted arylsulfonyloxy group, a substituted orunsubstituted alkylcarbonyloxy group or a substituted or unsubstitutedarylcarbonyloxy group.
 6. The method of claim 1, wherein R₂ is selectedfrom methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl,benzylsulfonyl, benzyl and phenyl.
 7. The method of claim 1, wherein thecompound of Formula (I) is selected from the group consisting of:5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2,5-bis{[(4-methylphenyl) sulfonyl]oxy}benzenesulfonic acid;5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;3-(2,5-dihydroxyphenyl)-2-propenoic acid;3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy)}phenyl)-2-propenoic acid;3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceuticallyacceptable salts and solvates thereof.
 8. The method of claim 7, whereinthe compound of Formula (I) is selected from:5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-hydroxy-5-{[(4-methylphenyl) sulfonyl]oxy}benzenesulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2,5-bis{[(4-methylphenyl) sulfonyl]oxy}benzenehomosulfonic acid, andpharmaceutically acceptable salts and solvates thereof.
 9. The method ofclaim 1, wherein the compound of Formula (I) is selected from:3-(2,5-dihydroxyphenyl)-2-propenoic acid;3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy)}phenyl)-2-propenoic acid;3-(2,5-bis {[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid, and pharmaceuticallyacceptable salts and solvates thereof.
 10. The method of claim 1,further comprising administration of at least one additional therapeuticagent.
 11. The method of claim 10, wherein the at least one additionaltherapeutic agent is selected from the group consisting of: diclofenac,T4 endonuclease, isotretinoin, acitretin, cidofoir, a corticosteroid, anantibiotic, an analgesic, an immunomodulator, including oralimmunomodulator such as tacrolimus and pimecrolimus, and topicalimmunomodulators; an immunosuppressant, an anti-angiogenic; aleukotriene modifier, an aminosalicylate, an anesthetic, a non-steroidalanti-inflammatory, a modifier of a solubilized interleukin receptor, aninhibitor of a tyrosine-kinase receptor, a protein kinase C inhibitor,and a combination of two or more thereof.
 12. The method of claim 1,wherein the compound is administered at least once per week.
 13. Themethod of claim 12, wherein the compound is administered at least onceper day.
 14. The method of claim 13, wherein the compound isadministered at least twice per day.
 15. The method of claim 1, whereinthe compound is present in a pharmaceutical composition in an amount ofat least about 1% w/w.
 16. The method of claim 15, wherein the compoundis present in a pharmaceutical composition in an amount of at leastabout 2.5% w/w.
 17. The method of claim 16, wherein the compound ispresent in a pharmaceutical composition in an amount of at least about5% w/w.
 18. The method of claim 1, wherein the compound is administeredover a period of at least about one week.
 19. The method of claim 18,wherein the compound is administered over a period of at least aboutfour weeks.
 20. The method of claim 1 comprising topical administrationof a compound of Formula (I) wherein R₁ is —CH═CH—(CH₂)_(p)Z, Zis-CO₂R₃; R₃ is methyl and p is 0.